A cell-free nutrient-supplemented perfusate allows four-day ex vivo metabolic preservation of human kidneys.

The growing disparity between the demand for transplants and the available donor supply, coupled with an aging donor population and increasing prevalence of chronic diseases, highlights the urgent need for the development of platforms enabling reconditioning, repair, and regeneration of deceased donor organs. This necessitates the ability to preserve metabolically active kidneys ex vivo for days. However, current kidney normothermic machine perfusion (NMP) approaches allow metabolic preservation only for hours. Here we show that human kidneys discarded for transplantation can be preserved in a metabolically active state up to 4 days when perfused with a cell-free perfusate supplemented with TCA cycle intermediates at subnormothermia (25 °C). Using spatially resolved isotope tracing we demonstrate preserved metabolic fluxes in the kidney microenvironment up to Day 4 of perfusion. Beyond Day 4, significant changes were observed in renal cell populations through spatial lipidomics, and increases in injury markers such as LDH, NGAL and oxidized lipids. Finally, we demonstrate that perfused kidneys maintain functional parameters up to Day 4. Collectively, these findings provide evidence that this approach enables metabolic and functional preservation of human kidneys over multiple days, establishing a solid foundation for future clinical investigations.

Endothelial to mesenchymal transition in kidney fibrosis.

Fibrotic disease are characterized by the uncontrolled accumulation of extracellular matrix (ECM) components leading to disruption of tissue homeostasis. Myofibroblasts as main ECM-producing cells can originate from various differentiated cell types after injury. Particularly, the process of endothelial-to-mesenchymal transition (endMT), describing phenotypic shifts of endothelial cells (ECs) to adopt a fully mesenchymal identity, may contribute to the pool of myofibroblasts in fibrosis, while leading to capillary rarefaction and exacerbation of tissue hypoxia. In renal disease, incomplete recovery from acute kidney injury (AKI) and the ensuing fibrotic reaction stand out as major contributors to chronic kidney disease (CKD) development. While the focus has largely been on impaired tubular epithelial repair as a potential fibrosis-driving mechanism, alterations in the renal microcirculation post-AKI, and in particular endMT as a maladaptive response, could hold equal significance. Dysfunctional interplays among various cell types in the kidney microenvironment can instigate endMT. Transforming growth factor beta (TGF-ß) signaling, with its downstream activation of canonical/Smad-mediated and non-canonical pathways, has been identified as primary driver of this process. However, non-TGF-ß-mediated pathways involving inflammatory agents and metabolic shifts in intercellular communication within the tissue microenvironment can also trigger endMT. These harmful, maladaptive cell-cell interactions and signaling pathways offer potential targets for therapeutic intervention to impede endMT and decelerate fibrogenesis such as in AKI-CKD progression. Presently, partial reduction of TGF-ß signaling using anti-diabetic drugs or statins may hold therapeutic potential in renal context. Nevertheless, further investigation is warranted to validate underlying mechanisms and assess positive effects within a clinical framework.

Do Patients with Psoriatic Arthritis Have More Severe Skin Disease than Patients with Psoriasis Only? A Systematic Review and Meta-Analysis.

BACKGROUND: Early identification of patients at risk of psoriatic arthritis (PsA) is essential to facilitate early diagnosis and improve clinical outcomes. Severe cutaneous psoriasis has been proposed to be associated with PsA, but a recent assessment of the evidence is lacking. Therefore, in this systematic review, we address the association of psoriasis skin severity with the presence and development of PsA. SUMMARY: We included articles from a review published in 2014 and supplemented these with recent literature by performing an additional systematic search to identify studies published between 1 January 2013 and 11 February 2021. A meta-analysis was performed when sufficient comparable evidence was available. Of 2,000 screened articles, we included 29 in the analysis, of which 16 were identified by our updated search. Nineteen studies reported psoriasis severity as psoriasis area and severity index (PASI), ten studies as body surface area (BSA), and two studies as "number of affected sites." Most studies show that more extensive skin disease is associated with the presence of PsA. The quantitative pooled analyses demonstrate higher PASI (mean difference [Δ] 1.59; 95% confidence interval [CI] 0.29-2.89) and higher BSA (Δ 5.31; 95% CI 1.78-8.83) in patients with PsA as compared to psoriasis patients without PsA. Results from prospective studies - that assess the risk of future development of PsA in psoriasis patients - were inconclusive. KEY MESSAGES: In patients with psoriasis, more severe skin involvement is associated with the presence of PsA, underpinning the importance of optimal dermatology-rheumatology collaboration in clinical care. There are insufficient data to support the use of psoriasis skin severity to predict the future development of PsA in psoriasis patients.

The use of local therapy in preventing urethral strictures: A systematic review.

BACKGROUND: Urethral stricture disease is a common problem amongst men in Western countries often leading to a decreased quality of life. Current endoscopic treatment procedure shows an unsatisfying stricture recurrence rate which could be improved by addition of local therapies. OBJECTIVES: To provide an overview of both preclinical and clinical studies in order to investigate current level of evidence on the addition of local therapy to improve urethral stricture recurrence rates after endoscopic procedures. METHODS: We performed a literature search in December 2020 and August 2021 using Cochrane, Embase, PubMed, Scopus and Web of Science and identified articles through combinations of search terms for 'urethral stricture disease', 'stricture formation' and 'local interventions'. We used the SYRCLE, RoB-2 and ROBINS-I tools to assess risk of bias across included studies. We did not perform a meta-analysis due to methodological differences between studies. RESULTS: We included 32 articles in the qualitative analysis, 20 of which were preclinical studies and 12 clinical studies. Regarding preclinical articles using an animal model, nearly all interventions showed to have a positive effect on either urethral fibrosis, urethral stricture formation and/or fibrotic protein expression levels. Here, immunosuppressants and chemotherapeutics seemed most promising for possible clinical purposes. Regarding clinical studies, mitomycin-C and hyaluronic acid and carboxymethylcellulose showed positive effects on urethral stricture recurrence rates with low to intermediate risk of bias across studies. However, the positive clinical effects of mitomycin-C and steroids seemed to decrease in studies with a longer follow-up time. CONCLUSION: Although local adjuvant use of mitomycin-C or hyaluronic acid and carboxymethylcellulose may carry clinical potential to improve urethral structure recurrence rates after endoscopic procedures, we believe that a large, well-designed RCT with a yearlong follow-up time is necessary to identify the true clinical value.

DNAM1 and TIGIT balance the T cell response, with low T cell TIGIT expression corresponding to inflammation in psoriatic disease.

Objectives: Signals at the contact site of antigen-presenting cells (APCs) and T cells help orchestrate the adaptive immune response. CD155 on APCs can interact with the stimulatory receptor DNAM1 or inhibitory receptor TIGIT on T cells. The CD155/DNAM1/TIGIT axis is under extensive investigation as immunotherapy target in inflammatory diseases including cancer, chronic infection and autoimmune diseases. We investigated a possible role for CD155/DNAM1/TIGIT signaling in psoriatic disease. Methods: By flow cytometry, we analyzed peripheral blood mononuclear cells of patients with psoriasis (n = 20) or psoriatic arthritis (n = 21), and healthy individuals (n = 7). We measured CD155, TIGIT, and DNAM1 expression on leukocyte subsets and compared activation-induced cytokine production between CD155-positive and CD155-negative APCs. We assessed the effects of TIGIT and DNAM1 blockade on T cell activation, and related the expression of CD155/DNAM1/TIGIT axis molecules to measures of disease activity. Results: High CD155 expression associates with tumor necrosis factor (TNF) production in myeloid and plasmacytoid dendritic cells (DC). In CD1c+ myeloid DC, activation-induced CD155 expression associates with increased HLA-DR expression. CD8 T cells - but not CD4 T cells - express high levels of TIGIT. DNAM1 blockade decreases T cell pro-inflammatory cytokine production, while TIGIT blockade increased T cell proliferation. Finally, T cell TIGIT expression shows an inverse correlation with inflammation biomarkers in psoriatic disease. Conclusion: CD155 is increased on pro-inflammatory APCs, while the receptors DNAM1 and TIGIT expressed on T cells balance the inflammatory response by T cells. In psoriatic disease, low TIGIT expression on T cells is associated with systemic inflammation.

First-line csDMARD monotherapy drug retention in psoriatic arthritis: methotrexate outperforms sulfasalazine.

OBJECTIVES: Conventional synthetic DMARDs (csDMARDs) are the first-line treatment for PsA, but there is conflicting data regarding their efficacy and scarce reports describing the duration of use (drug retention) of csDMARD in this population. Their position in treatment recommendations is a matter of growing debate due to the availability of alternative treatment options with higher levels of evidence. We aimed to study drug retention and predictors for drug retention among PsA patients receiving first-line csDMARD monotherapy. METHODS: Retrospective cohort study in DMARD-naïve adult PsA patients in whom a first csDMARD was prescribed as monotherapy primarily to treat PsA-related symptoms. The main outcome was time to failure of the csDMARD (i.e. stopping the csDMARD or adding another DMARD). RESULTS: A total of 187 patients were included, who were mainly prescribed MTX (n = 163) or SSZ (n = 21). The pooled median drug retention time was 31.8 months (interquartile range 9.04-110). Drug retention was significantly higher in MTX (median 34.5 months; interquartile range 9.60-123) as compared with SSZ-treated patients (median 12.0 months; interquartile range 4.80- 55.7) (P =0.016, log-rank test). In multivariable Cox regression, the use of MTX and older age were associated with increased retention. The main reasons for treatment failure were inefficacy (52%) and side effects (28%). Upon failure, MTX treated patients were more commonly, subsequently treated with a biologic DMARD compared with SSZ (P < 0.05). CONCLUSION: MTX outperforms SSZ as a first-line csDMARD in DMARD-naïve PsA patients with respect to monotherapy drug retention in daily clinical practice.